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Purpose: This study evaluates beam angles used to generate highly individualized proton therapy treatment plans for patients eligible for carbon ion radiotherapy (CIRT). Methods and Materials: We retrospectively evaluated patients treated with pencil beam scanning intensity modulated proton therapy from 2015 to 2020 who had indications for CIRT. Patients were treated with a 190° rotating gantry with a robotic patient positioning system. Treatment plans were individualized to provide maximal prescription dose delivery to the tumor target volume while sparing organs at risk. The utilized beam angles were grouped, and anatomic sites with at least 10 different beam angles were sorted into histograms. Results: A total of 467 patients with 484 plans and 1196 unique beam angles were evaluated and characterized by anatomic treatment site and the number of beam angles utilized. The most common beam angles used were 0° and 180°. A wide range of beam angles were used in treating almost all anatomic sites. Only esophageal cancers had a predominantly unimodal grouping of beam angles. Pancreas cancers showed a modest grouping of beam angles. Conclusions: The wide distribution of beam angles used to treat CIRT-eligible patients suggests that a rotating gantry is optimal to provide highly individualized beam arrangements.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

Abstract INTRODUCTION Medulloblastomas (MB) are embryonal tumors arising in the cerebellum, predominantly affecting pediatric patients. Recognition of molecularly defined subgroups has advanced management. Factors influencing the prognosis and management of adult MB patients remain poorly understood. METHODS We retrospectively reviewed our experience with adult (> 18 years at initial diagnosis) MB patients, diagnosed between 1992-2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (Log-rank test assessing for group differences) were performed for univariate survival analysis with cox regression used for multivariate (subgroup, age, gender, disseminated disease, extent of resection) analyses. RESULTS Our cohort included 76 adult MB patients (62% male), with a median age of 31.7 years (range: 18-66) at diagnosis, and median follow-up of 7.7 years (range: 0.6-26.9). 58 patients had sufficient tissue for molecular characterization by immunohistochemistry and corresponded to the SHH-activated (n=37; 64%), non-WNT/non-SHH (n=12; 21%), WNT-activated (n=9; 15%) subgroups. At initial diagnosis, all patients underwent radiotherapy, with 97% (n=66) receiving craniospinal irradiation with a boost either to the posterior fossa (75%) or tumor bed (22%); and underwent gross total resection (n=51; 67%) and chemotherapy (n=56; 75%). Median overall survival (OS) for the whole cohort was 14.8 years (93% 2-year OS; 86% 5-year OS; 64% 10-year OS) and was longer for younger patients (< 30: > 15.4 years, > 30: 9.9 years; Log-rank p< 0.001). No significant OS difference was identified by MB molecular subgroup (SHH, TP53-wt: 14 years, WNT: 11.4 years, non-WNT/non-SHH: > 14.8 years; Log-rank p=0.1167) or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses. DISCUSSION We report one of the largest retrospective cohorts in adult MB patients with molecular subtyping. Survival and molecular subgroup frequencies were similar to previous reports. Survival was longer for younger patients and was not significantly different by MB molecular subgroup or extent of resection.

The management of clival chordoma in our group shifted around 2013 to mostly endoscopic, and proton beam was introduced for our multidisciplinary team. Consecutive patients who had surgical resection from 1987 to 2021 were reviewed. A total of 58 patients (39 patients after 2013) were analyzed. The mean tumor size was 3.7 cm, and the most common location was the upper clivus (43%). Compared to before 2013, after 2013, the endoscopic endonasal approach was more common (90%, p < 0.001), and more gross or near total resections (64%, p = 0.002) were attained. Ten cases (17%) were revision surgeries referred from elsewhere, and three cases (5%) underwent additional surgery elsewhere before adjuvant radiation. The postoperative cerebrospinal fluid leak occurred in 7%. Post-operative new cranial nerve deficits occurred in 32% before 2013, compared to 2.6% after 2013 (p = 0.004). For cases before 2013, 10 patients (53%) recurred during the median follow-up of 144 months (mean, 142 months), whereas for cases after 2013, seven patients (18%) recurred with a median follow-up of 35 months (mean, 42 months). 5-year progression-free survival was 58%, and 5-year overall survival was 87%. A specialized multidisciplinary team improved the resection rate compared to a historical cohort with an excellent morbidity profile.

Abstract Diffuse midline glioma (DMG) of the pons remains the leading cause of death among pediatric patients with brain tumors, despite numerous attempts to intensify treatment. While standard treatment includes 54Gy in 30 fractions of radiation over six weeks of time, nearly all patients progress within the treatment field, and many experience symptomatic radionecrosis with steroid dependence. Symptom improvement typically begins after 20Gy to the tumor. Both hypofractionation and reirradiation after recurrence have been found to be safe for patients with DMG. Our study aims to enroll patients with newly diagnosed pontine DMG aged &gt;1 year (no maximum age), and collect molecular information about DMG via stereotactic biopsy, followed by a short 2 week course of 25Gy in 10 fractions of radiation, with volumes guided by MRI with tractography reconstruction and FDOPA PET radiotracer uptake. Patients are followed closely and can complete the 25Gy in 10 fraction radiation course up to 3 times total for meeting radiographic and clinical progression criteria. Our primary endpoint is to estimate the time to progression from diagnosis to after receiving the second 25Gy course, and to compare this to the historical 7 month standard from diagnosis to progression after one 54Gy course. We aim to improve the time interval where patients are asymptomatic at home while minimizing time receiving daily treatments. Other endpoints will include the patient quality of life, caregiver quality of life, PFS intervals after each course, overall survival, and toxicity.

AbstractBackgroundPediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes.ProcedureSurvivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills.ResultsAge at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2(1) = 38.67, p < .001; χ2(1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = −1.99, p = .05). Tumor diameter predicted social skills (t = −2.07, p < .05).ConclusionsRegardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Abstract Background Brainstem toxicity after radiation therapy (RT) is a devastating complication and a particular concern with proton radiation (PBT). We investigated the incidence and clinical correlates of brainstem injury in pediatric brain tumors treated with PBT. Methods All patients &lt;21 years with brain tumors treated with PBT at our institution from 2007–2019, with a brainstem Dmean &gt;30 Gy and/or Dmax &gt;50.4 Gy were included. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia, and/or motor weakness with corresponding radiographic abnormality within brainstem. Results A total of 595 patients were reviewed and 468 (medulloblastoma = 200, gliomas = 114, ependymoma = 87, ATRT = 43) met our inclusion criteria. Median age at RT was 6.3 years and median prescribed RT dose was 54Gy [RBE]. Fifteen patients (3.2%) developed SBI, at a median of 4 months after RT. Grades 2, 3, 4, and 5 brainstem injuries were seen in 7, 5, 1, and 2 patients respectively. Asymptomatic radiographic changes were seen in 51 patients (10.9%). SBI was significantly higher in patients with age ≤3 years, female gender, ATRT histology, patients receiving high-dose chemotherapy with stem cell rescue, and those not receiving craniospinal irradiation. Patients with SBI had a significantly higher V50–52. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤57 Gy, Dmean ≤52.4 Gy, and V54≤10%). There was a trend towards decrease in SBI from 4.4% (2007-2013) to 1.5% (2014–2019) (P = .089) without affecting survival. Conclusion Our results suggest a low risk of SBI after PBT for pediatric brain tumors, comparable to photon therapy. A lower risk was seen after adopting strict brainstem dose constraints.

Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year.